HK1096847B - Sustained analgesia achieved with buprenorphine - Google Patents

Description

Sustained analgesia achieved with buprenorphine

This application is a divisional application of the chinese patent application entitled "achieving sustained analgesia with buprenorphine" filed 24/2/1998 under the application number CN 98802461.4.

Technical Field

The present invention relates to the use of buprenorphine (buprenorphine) for the treatment of pain in patients for the long-term effective treatment of pain.

Background

The meaning of the sustained release pharmaceutical formulation is: after administration of a sustained release formulation of a drug, a longer pharmacological effect may be provided than is typically experienced after administration of an immediate release formulation of the drug. These longer term efficiencies can provide many of the inherent therapeutic effects not achievable with corresponding immediate release formulations. The effects of extended analgesia provided by extended release oral analgesics have become widely recognized, and oral opioid analgesic releases are commercially available.

Prolonged analgesia is particularly desirable in patients with moderate to severe pain (e.g., cancer patients). Existing oral formulations provide an effect that lasts, for example, about 12 hours (sometimes 24 hours), so that the patient need only take 1 to 3 times a day. For example, morphine, which has been identified as the prototype opioid analgesic, has now been formulated as a twice daily oral sustained release formulation (e.g., MS)Tablets, available from The Purdue fredick company).

Another method of sustained delivery of pharmaceutically active agents is transdermal drug delivery devices, such as transdermal patches. Transdermal patches typically contain a pharmaceutically active agent (e.g., an opioid analgesic), a reservoir or matrix containing the opioid or other active ingredient, and an adhesive that adheres the transdermal device to the skin, thereby allowing the active agent to permeate from the device through the patient's skin. Once the active agent penetrates the skin layer, the drug is absorbed by the bloodstream and can exert the desired therapeutic effect (e.g., analgesic effect) of the drug.

Transdermal drug delivery devices using opioid analgesics as the active ingredient have been considered. For example, commercially available opioid analgesic transdermal formulations are(available from Janssen Pharmaceutical; the active ingredient is fentanyl citrate). It is said that the first and second substrates,the patch can provide sufficient analgesia for up to 48 to 72 hours (2 to 3 days).

Buprenorphine, a partially synthetic opiate, has also been recognized as a protracted analgesic. Although other types of transdermal formulations of opioid analgesics have been reported in the literature (e.g., fentanyl citrate, as described above), the transdermal buprenorphine delivery device is of particular interest because buprenorphine is a potent, partially-acting opioid analgesic with desirable therapeutic properties. For example, buprenorphine is 50-100 times more effective than morphine, but the treatment index is much safer than morphine (see Wallenstein SL et al, Cross-test in clinical analgesic testing: buprenorphine and morphine research, Pharmacotherapy G (5): 225-. Furthermore, some of the agonistic properties of buprenorphine are useful in the treatment of opioid addiction.

Several types of transdermal formulations of buprenorphine are reported in the literature. See, for example, U.S. Pat. No.5,240,711(Hille et al), U.S. Pat. No.5,225,199(Hidaka et al), U.S. Pat. No.5,069,909(Sharma et al), U.S. Pat. No.4,806,341(Chien et al), and U.S. Pat. No.5,026,556(Drust et al), all of which are incorporated herein by reference.

Buprenorphine has low oral bioavailability and has been recognized by some skilled in the art as addicted to other narcotics (see, e.g., U.S. patent No.5,240,711 (to Hille et al)) and induces resistance (see, e.g., U.S. patent No.5,613,958 (to Kochinke et al)). As reported by Hille et al, the experts' opinions were: the form of drug administration creates a risk of addiction, producing blood levels above that required immediately after administration of a drug (e.g. buprenorphine), followed by a substantial decline (successively causing pleasure, followed by ineffective pain treatment), thereby allowing the patient to begin the desired next administration (known as "iatrogenic" addiction). In the case of buprenorphine, Hille et al report that continuous infusion would be considered the most appropriate way to avoid this iatrogenic addiction by providing a constant blood level; however, continuous infusion requires the physician to control and insert a cannula, which may cause irritation at the site. Hille et al believe that this problem can be overcome by employing a transdermal delivery device which comprises buprenorphine or a pharmaceutically acceptable salt thereof and which releases the drug in a controlled manner over at least 24 hours, ensuring that the buprenorphine does not significantly degrade when the transdermal delivery device is stored, thereby further ensuring that the desired amount of buprenorphine penetrates the skin in vivo.

Kochinke et al describe a transdermal device for regulating the administration of tolerance-inducing drugs. Buprenorphine is considered such a drug. The device is designed to deliver a drug through the skin of a patient through a three-phase drug delivery profile. The first phase begins with the application of the patch and ends 2-10 hours after the application of the patch, during which plasma levels of the drug are obtained. Therapeutic plasma levels of the drug are maintained in a second phase following this phase. The second phase begins at about 2 to 10 hours after patch application and ends 8-18 hours after application. In the third phase, sub-therapeutic levels of drug are maintained by the patch's inherent design and/or removal. The principle of the drug delivery curve of Kochinke et al is: an initial high blood level followed by a reduced dose (down to a sub-therapeutic level) may be more effective than maintaining the blood level at a higher or lower level (i.e., sub-therapeutic level) throughout the administration period. With this phase of regulation (profile), it is said that the development of resistance to the administered drug is prevented or greatly reduced.

Despite these advances in the art, there remains a need for a method of treating patients with buprenorphine that provides effective levels of analgesia for buprenorphine over an extended period of time while eliminating or minimizing dependency, drug resistance and side effects, thereby providing a safe and effective method of pain treatment. Moreover, there is a need for a transdermal formulation of opioid analgesics, preferably buprenorphine, that provides effective levels of analgesia for buprenorphine for a period of time exceeding that contemplated or practiced in the art, while eliminating or minimizing dependency, drug resistance and side effects, thereby providing a safe and effective method of pain treatment.

Disclosure of Invention

It is an object of the present invention to provide a method and a pharmaceutical preparation (medicament) which enables buprenorphine plasma concentrations to be lower than those obtained by prior art methods for an extended period of time, while still being effective in the treatment of pain.

It is a further object of the present invention to provide methods and pharmaceutical formulations (medicaments) for treating pain in patients with buprenorphine which provide for delayed and effective treatment of pain while possibly reducing the side effects, dependence and resistance experienced by patients on chronic treatment with narcotics such as buprenorphine.

It is a further object to provide methods and pharmaceutical formulations (medicaments) for treating pain in a patient by utilizing a transdermal delivery device containing buprenorphine in a manner that maximizes the administration period (i.e., the interval during which the transdermal delivery device maintains contact with the skin) and minimizes plasma concentrations in the patient's body during the administration period while also surprisingly maintaining effective pain treatment.

It is also an object of the present invention to provide methods and pharmaceutical formulations (medicaments) for treating opioid addicted patients by gradually reducing the plasma concentration of the opioid in the patient's plasma while providing effective plasma concentrations in those patients to be detoxified.

In accordance with the above and other objects of the invention, the invention is directed, in part, to the surprising result that increasing the plasma concentration of buprenorphine at a rate of about first order (i.e., indicative of first order pharmacokinetics) over a period of about 3 days (e.g., 72 hours) with a buprenorphine medicament, and then maintaining the plasma concentration of buprenorphine in accordance with substantially zero order (i.e., indicative of zero order) pharmacokinetics over a delay period of at least about 2 days (e.g., 48 hours) provides effective pain treatment.

The invention also relates to the use of buprenorphine in the manufacture of a medicament for a method of effectively treating pain in a human, the method comprising: buprenorphine is administered to a human patient such that the following mean plasma concentrations are obtained over a 72 hour dosing period: at about 6 hours after the start of the dosing period, the mean plasma concentration is about 0.3-113 pg/ml; at about 12 hours after the start of the dosing period, the mean plasma concentration is about 3-296 pg/ml; at about 24 hours after the start of the dosing period, the mean plasma concentration is about 11-644 pg/ml; at about 30 hours after the start of the dosing period, the mean plasma concentration is about 13-630 pg/ml; at about 36 hours after the start of the dosing period, the mean plasma concentration is about 15-715 pg/ml; at about 48 hours after the start of the dosing period, the mean plasma concentration is about 20-984 pg/ml; at about 60 hours after the start of the dosing period, the mean plasma concentration is about 21-914 pg/ml; at about 72 hours after the start of the dosing period, the mean plasma concentration is about 24-850 pg/ml; buprenorphine is then administered so that a mean plasma concentration of about 19-850pg/ml is maintained for at least 48 hours thereafter. In certain preferred embodiments, the dosing period is maintained for more than 7 days.

The invention also relates to the use of buprenorphine in the preparation of a medicament, wherein the buprenorphine is contained in a transdermal delivery device which, when placed on the skin of a patient, releases buprenorphine at a rate such that a maximum plasma concentration of about 20pg/ml to about 850pg/ml is achieved over an administration period of about 72 hours (depending on the dose level required to maintain analgesia in the particular patient), the medicament providing a buprenorphine plasma concentration in the patient above the minimum effective concentration of buprenorphine when the medicament is maintained on the skin of the patient for at least 24 hours, thereby enabling the patient to continue to undergo effective pain treatment for this additional administration period.

The invention also relates to the use of buprenorphine in the manufacture of a medicament for a method of effectively treating pain in a human, the method comprising: buprenorphine was administered transdermally to human patients to obtain the following average relative release rates: the mean relative release rate from the beginning of the administration period to about 72 hours thereafter is about 3-86 μ g/hour; the mean relative release rate from about 72 hours after the start of the dosing period to at least about 120 hours after the start of the dosing period is about 0.3-9 μ g/hr. In certain preferred embodiments, the mean relative release rate is from about 0.3 μ g/hr to about 9 μ g/hr from 72 hours after the beginning of the dosing period to at least about 168 hours after the beginning of the dosing period.

The invention also relates to the use of buprenorphine in the manufacture of a medicament for a method of effectively treating pain in a human, the method comprising: transdermally administering buprenorphine to the human patient such that the average relative release rate of buprenorphine is about 3-86 μ g/hr over a period of about 72 hours after application of the transdermal drug delivery device; subsequently, a mean relative release rate of about 0.3-9 μ g/hr is provided (either with the same transdermal delivery device or with a different transdermal delivery device when the device is removed) from about 72 hours after the beginning of the administration period to at least about 120 hours after the beginning of the administration period (preferably to at least about 168 hours after the beginning of the administration period).

The invention described herein contemplates the use of a buprenorphine transdermal agent which provides an analgesia of about 72 hours, which provides a drug release rate which is generally first order pharmacokinetic over the 72 hours when applied to the skin, and the fact that these transdermal delivery devices provide a substantial reduction in buprenorphine release rate after the first 72 hours, but still provide relatively little but sufficient buprenorphine release to maintain the desired analgesia and plasma levels in the patient for at least (e.g., preferably) 48 hours by bringing the transdermal delivery device into contact with the patient's skin for these advantageous additional administration periods (which may be as long as 96 hours or more). Surprisingly, it has been found that these transdermal delivery devices exhibit substantially zero order release after about 72 hours from the beginning of the delivery period, and thus they are able to maintain effective buprenorphine plasma concentrations for a longer period of time than previously reported in the prior art. However, the method of the present invention also contemplates the possibility of using a first transdermal delivery device to provide the desired primary pharmacokinetics and then removing the first transdermal delivery device and replacing it with a second device to provide the desired substantially zero-order pharmacokinetics over a longer period of time (e.g., at least about 24 hours, preferably at least about 48 hours, and most preferably about 96 hours). The second buprenorphine pharmaceutical agent may be a second transdermal delivery device providing the aforementioned average relative release rate of about 0.3-9 mug/hr. On the other hand, the second buprenorphine medicament may even take a different form of administration, for example by continuous infusion.

The invention also relates in part to the use of buprenorphine in the preparation of a medicament for the effective treatment of pain in a patient, the method comprising applying to the skin of the patient a transdermal delivery agent containing buprenorphine, the transdermal delivery agent delivering buprenorphine substantially according to first order kinetics so as to provide a mean plasma concentration of about 24 to 850pg/ml 3 days after application, the transdermal buprenorphine agent remaining in contact with the skin of the human patient for about 2 to 6 days, thereby allowing the patient to continue to receive effective analgesia from the transdermal buprenorphine formulation.

The invention also relates to the use of buprenorphine in the preparation of a medicament for treating pain in a human patient by applying a transdermal delivery agent containing buprenorphine to the skin of the patient and maintaining the transdermal delivery agent in contact with the skin for an administration period of 3 days, the transdermal delivery agent containing buprenorphine in an amount sufficient to provide effective analgesia in the patient for about 3 days, wherein the transdermal delivery agent is in contact with the skin of the patient for about 2 to 6 more days in addition to the 3-day administration period.

The invention also relates in part to the use of buprenorphine in the manufacture of a medicament effective in treating pain in a patient, the method comprising: applying a transdermal drug delivery device containing buprenorphine as an active ingredient to the skin of the patient, the device releasing buprenorphine at a first rate over a three day dosing period, thereby achieving a maximum plasma concentration of about 20pg/ml to about 1052 pg/ml; the transdermal delivery device is maintained on the skin of the patient for an additional administration period of at least two days during which the transdermal delivery device exhibits substantially zero order kinetics such that the patient experiences analgesia for the additional at least two days of the administration period.

The invention also relates in part to the use of buprenorphine in the manufacture of a medicament effective in treating pain in a patient, the method comprising: applying a transdermal drug delivery device containing buprenorphine as the active ingredient to the skin of the patient, the device releasing the drug delivery in first order kinetics (e.g., the rate of buprenorphine release over the first three day dosing period) such that a mean plasma concentration of about 21-1052pg/ml is obtained after about 72 hours of administration of said transdermal drug delivery device; the transdermal delivery device is maintained on the skin of the patient for an additional at least two dosing periods during which the transdermal delivery device is released with zero order kinetics such that an average relative release rate of about 0.3 to 9 μ g/hr is maintained over the additional at least two dosing periods. In certain preferred embodiments, the mean plasma concentration obtained about 72 hours after application of the transdermal delivery device is about 85 to 263 pg/ml; the mean relative release rate was maintained at about 13-21 μ g/hr during the at least two additional dosing periods. In another preferred embodiment, the mean plasma concentration obtained about 72 hours after application of the transdermal delivery device is about 20 to 66 pg/ml; the mean relative release rate was maintained at about 0.3-0.6 μ g/hr during the at least two additional dosing periods. In another preferred embodiment, the mean plasma concentration obtained about 72 hours after application of the transdermal delivery device is about 42 to 132 pg/ml; the mean relative release rate was maintained at about 0.7-1 μ g/hr during the at least two additional dosing periods. In another preferred embodiment, the mean plasma concentration obtained about 72 hours after application of the transdermal delivery device is about 169 pg/ml to about 526 pg/ml; the mean relative release rate was maintained at about 2-4 μ g/hr during the at least two additional dosing periods. In another preferred embodiment, the mean plasma concentration obtained about 72 hours after application of the transdermal delivery device is about 254 to 789 pg/ml; the mean relative release rate was maintained at about 4-7 μ g/hr during the at least two additional dosing periods. In yet another preferred embodiment, the mean plasma concentration achieved after about 72 hours of application of the transdermal delivery device is about 339 to 1052 pg/ml; the mean relative release rate was maintained at about 5-9 μ g/hr during the at least two additional dosing periods.

The invention also relates to the use of buprenorphine in the manufacture of a medicament for use in a method of treating an opioid addiction, the method comprising: administering transdermally buprenorphine (via a buprenorphine transdermal delivery device) to a human patient, the rate of drug release being generally first order pharmacokinetic over 72 hours when applied to the skin, such that an addict achieves a buprenorphine plasma concentration of about 1000 to 10,000 μ g/ml (preferably about 5000 to 8000 μ g/ml) about 72 hours after application of the buprenorphine transdermal delivery device; the transdermal delivery device is then maintained in contact with the skin of the addict such that the average relative release rate exhibits (near) zero order kinetics for an additional administration period of at least about 48 hours to provide the desired therapeutic effect (e.g., detoxification). In a preferred embodiment, the transdermal delivery device is maintained in contact with the skin of the addict for about 7 days.

Although chronic pain can often be treated with a combination of "mild" analgesics and non-pharmacological interventions, selected patients continue to experience unacceptably severe pain. Some patients with chronic pain cannot tolerate therapeutic doses of "mild" analgesics, while others develop pain that is severe to the extent that "strong" analgesics intended for subacute or chronic use are used.

The term "strong" analgesics includes, inter alia, several classes of opioid analgesics, including partial agonists. Parenteral buprenorphine (protocol V drug under the Controlled Substances Act) is just one example of a partial agonist opioid analgesic currently marketed in the united states.

Partial agonists provide some therapeutic benefits in many patients compared to morphine-like agonists and agonist-antagonist mixtures. For example, unlike agonist-antagonist mixtures (e.g., analgesic, naltrexone), buprenorphine avoids psychomimetic side effects; buprenorphine has a relatively low dose-response relationship to respiratory depression and a less abuse liability than agonists such as morphine and fentanyl citrate.

The chemical name of buprenorphine is 21-cyclopropyl-7-alpha- [ (S) -1-hydroxy-1, 2, 2-trimethylpropyl]6, 14-endo-ethano-6, 7, 8, 14-tetrahydrooripavine. The buprenorphine base has a molecular weight of 467.7; has the empirical formula ofC₂₉H₄1NO₄。

The structural formula of buprenorphine is shown below:

buprenorphine is an opioid partial agonist that has many of the effects of opioid agonists (e.g., analgesic effects). There has been detailed a description of the "highest effect" of buprenorphine in analgesia (i.e., increasing the dose does not increase the analgesic effect) in many animal models. It is highly lipophilic and slowly dissociates from opioid receptors. Buprenorphine is considered in the art as a partial agonist of the mu opioid receptor in the Central Nervous System (CNS) and peripheral tissues. It is also believed that buprenorphine reacts with μ and κ₁The affinity for receptor binding is higher and the affinity for δ receptor binding is lower. Intrinsic agonistic activity at the kappa receptor appears to be limited, and most evidence suggests that buprenorphine has antagonistic activity at the kappa receptor. The lack of kappa agonism is responsible for the lack of dysphoric and psychomimetic effects common in buprenorphine agonists. Other studies have shown that the opioid antagonistic effect of buprenorphine may be mediated through interaction with the delta opioid receptor.

It is known in the art that buprenorphine binds slowly to the μ receptor and dissociates slowly. It is believed that the high affinity of buprenorphine for the μ receptor and its slow binding and dissociation to the receptor may explain the prolonged duration of analgesic action and, in part, the limited body-dependent potential seen with this drug. High affinity binding may also account for the fact that buprenorphine blocks μ -potentiation of other opioids administered.

Like other opioid agonists, buprenorphine produces dose-related analgesia. The exact mechanism has not been fully explained, but it appears that the analgesic effect is due to the high affinity of buprenorphine for the μ receptors (and possibly also the kappa opioid receptors) in the CNS. Drugs may also alter the pain threshold (the threshold for penetrating nerve endings to toxic stimuli). By weight, the analgesic potency of parenteral buprenorphine appears to be about 25 to 50 times that of parenteral morphine, about 200 times that of analgesic neomycin, and about 600 times that of meperidine. Buprenorphine produces sex-related differences in analgesia, and women require far less drug than men for adequate analgesia.

For a study of transdermal delivery of buprenorphine through cadaver skin see Roy, Samir D et al, "transdermal delivery of buprenorphine through cadaver skin," Journal of pharmaceutical Sciences, Vol.83, pp.126-130 (1994), which is incorporated herein by reference. For a discussion of buprenorphine pharmacokinetics resulting from the application of fillable transdermal therapeutic devices, see Wilding, i.r. et al, "evaluation of pharmacokinetics of buprenorphine administered transdermally in humans", International Journal of pharmaceuticals, 132(1996), pages 81-87, incorporated herein by reference. For a discussion of the penetration of buprenorphine and its alkyl esters, see Imoto et al, "transdermal prodrug concept: the effect of buprenorphine and its alkyl esters on penetration through the skin and vehicle of hairless mice, Bio1.pharm. Bull., 19(2)263-267(1996), which is incorporated herein by reference.

Buprenorphine has a lower abuse liability than full agonist opioids. Although infrequent, buprenorphine also produces limited physical dependence, with signs and symptoms of mild withdrawal after discontinuation of long-term treatment with a single drug. Because buprenorphine binds to and dissociates from the μ receptor slowly, drug elimination in the CNS is prolonged following a sudden interruption; thus, the signs and symptoms of acute withdrawal are not as intense as those produced by morphine, and are delayed in appearance.

Buprenorphine produces many opioid subjective and objective effects in patients with physical dependence on opioids; however, this drug may not be a satisfactory alternative to opioid agonists in all opioid-dependent patients. It is reported that little, if any, tolerance is developed for the opioid agonist activity of the drug.

Buprenorphine may produce psychological dependence. Buprenorphine is a partial opioid agonist with behavioral and psychological effects similar to morphine. However, unlike the analgesic drugs, buprenorphine rarely causes psychomimetic effects. Like other opioid agonists, buprenorphine may increase cerebrospinal fluid pressure.

The pharmacokinetics of parenteral and sublingual buprenorphine administration are known. Intravenous administration of a single dose of about 0.3mg buprenorphine has been shown to provide a mean peak plasma drug concentration of about 18ng/ml in about 2 minutes; after about 5 minutes and about 3 hours, the plasma concentration was reduced to about 9 and about 0.4ng/ml, respectively. The second dose, 0.3mg, was administered intramuscularly 3 hours after the initial intravenous administration, with the mean peak plasma buprenorphine concentration being about 3.6ng/ml over about 2 to 5 minutes and decreasing to 0.4ng/ml after about 3 hours. About 10 minutes after administration, the plasma concentration of buprenorphine is similar to that after intravenous or intramuscular injection.

Parenteral solution of buprenorphine hydrochloride (0.3mg buprenorphine/ml) in an amount sufficient to reduce the concentration of buprenorphine in the solutionFrom Reckitt&Colman, for intramuscular and intravenous administration. A typical adult (age 13 years and older) dose is 0.3mg im or IV administered every 6 to 8 hours, as needed for moderate to severe pain. The dosage for children aged 2 to 12 years is 2-6 μ g/kg body weight every 4 to 6 hours. It is believed that the increased frequency of dosing in children is due to the higher buprenorphine clearance in children compared to adults. The mean duration of the analgesic effect is generally 6 hours after intramuscular or intravenous administration of a single dose of 0.2-0.3mg or 2 to 4 μ g/kg; however, it has been reported in some studies that the mean duration of analgesic action after intramuscular administration of a single dose of 0.2-0.6mg is 4 to 10 hoursIn this case, the duration is 2 to 24 hours after intravenous administration of a single dose of 0.3mg or 2-15. mu.g/kg.

For reference, mean peak plasma buprenorphine concentrations, time to peak concentrations, and systemic availability of single doses of buprenorphine of 0.4-0.8mg administered sublingually have been reported by Cowan, Alan and Lewis John, W. (buprenorphine: resistance to drug abuse with a unique opioid, Wiley-Liss, Inc., New York, 137-147 (1995)), which are all incorporated herein by reference. Reported Cmax of 0.50 ± 0.06ng/ml for 0.4mg sublingual dose; tmax is 210 +/-40 minutes; the systemic utilization rate is 57.7% + -6. Cmax is 1.04 + -0.27 ng/ml for a sublingual dose of 0.8 mg; tmax is 192 +/-49 minutes; the systemic utilization rate is 54.1% + -12.7.

A common sublingual analgesic dose of buprenorphine has been previously reported to be 0.2-0.4mg per 8 hours (e.g., Kuhlman, JJ, etc.,J Analyt Toxicol 1996；20(10)). For a transdermal patch providing a nominal delivery rate of about 12.5 μ g/hour, the total buprenorphine administered over a 24 hour period is about 0.3mg, while the sublingual equivalent dose over the same period is about 0.6 mg. For a transdermal drug delivery device (e.g., transdermal patch) that provides a nominal delivery rate of about 25 μ g/hour, the total buprenorphine administered over a 24 hour period is about 0.6mg, while the sublingual equivalent dose over the same period is about 1.2 mg. For a transdermal patch providing a nominal delivery rate of about 50 μ g/hour, the total buprenorphine administered over a 24 hour period is about 1.2mg, while the sublingual equivalent dose over the same period is about 2.4 mg. It is expected that one of ordinary skill in the art will know that, regardless of the mode of administration, an equivalent dose to achieve the buprenorphine plasma concentrations of the invention set forth herein can be determined by simple pharmaceutical calculation. In the discussion herein, a comparison is made between transdermal and sublingual doses.

The effects of buprenorphine in distribution to human tissues and fluids are not well documented. After oral or intramuscular administration in rats, buprenorphine is distributed to the liver, brain, placenta and gastrointestinal tract; the highest concentrations were obtained in the liver after 10 or 40 minutes of oral or intramuscular administration, respectively. The rate of buprenorphine extraction from the liver was about l. The drug and its metabolites are distributed into the bile. Following intravenous administration in humans, the drug rapidly partitions into the cerebrospinal fluid ("CSF") (within minutes). The CSF buprenorphine concentration appears to be about the concurrent plasma concentration d 15 or 25%. About 96% of the buprenorphine binds to plasma proteins (mainly alpha and beta globulins); the drug appears to not substantially bind albumin.

Buprenorphine is metabolized almost entirely in the liver, primarily by N-dealkylation, to form norbuprenorphine (N-dealkylated buprenorphine); buprenorphine and norbuprenorphine are also coupled with glucuronic acid. Like metabolites of other opioid agonists, norbuprenorphine may have poor analgesic activity; however, the analgesic activity of buprenorphine metabolites has not been investigated. Buprenorphine and its metabolites are excreted mainly in the feces by bile elimination and also in the urine. Buprenorphine excreted in feces is mainly an unaltered drug; a small amount of norbuprenorphine is also excreted in the feces. It is believed that the drug and its metabolites undergo enterohepatic circulation. Norbuprenorphine exhibits excretion primarily in urine at a lower rate than its parent drug. The total plasma clearance rate of buprenorphine in conscious post-operative patients is reported to be about 1.28 l/min. Limited data indicate that buprenorphine pharmacokinetics in children vary greatly from individual to individual; however, drug clearance appears to be increased in children (e.g., children 5 to 7 years old) compared to adults. In pediatric patients, the optimal buprenorphine dosing interval must be shortened.

Achieving effective analgesic plasma opioid concentrations in patients is very complex and involves a number of factors, including the inherent chemical and physical properties of the opioid itself. Other considerations include in vivo metabolism, individual patient response and tolerance. However, there is a "minimum effective analgesic concentration" (MEAC) in plasma for a particular opioid below which analgesia is not provided. Plasma opioid levels are associated with analgesic effects. Higher plasma levels are often associated with greater pain relief, as are the likelihood and severity of possible side effects. In certain preferred embodiments of the invention, when treating moderate or severe pain in a patient, buprenorphine is administered such that the following mean plasma concentrations are obtained over a 72 hour dosing period: at about 6 hours after the start of the dosing period, the mean plasma concentration is about 0.3-113 pg/ml; at about 12 hours after the start of the dosing period, the mean plasma concentration is about 3-296 pg/ml; at about 24 hours after the start of the dosing period, the mean plasma concentration is about 7-644 pg/ml; at about 36 hours after the start of the dosing period, the mean plasma concentration is about 13-753 pg/ml; at about 48 hours after the start of the dosing period, the mean plasma concentration is about 16-984 pg/ml; at about 60 hours after the start of the dosing period, the mean plasma concentration is about 20-984 pg/ml; at about 72 hours after the start of the dosing period, the mean plasma concentration was about 20-1052 pg/ml. Buprenorphine is then administered such that the mean plasma concentration is maintained at about 19 to 1052pg/ml for at least 48 hours thereafter. In certain preferred embodiments, the method further comprises maintaining buprenorphine administration at zero order kinetics for at least 48 hours thereafter. Preferably, the mean plasma concentrations are maintained after 72 hours of the administration period as follows: at about 96 hours after the start of the dosing period, the mean plasma concentration is about 23-1052 pg/ml; at about 120 hours after the start of the dosing period, the mean plasma concentration is about 23-1052 pg/ml; at about 144 hours after the start of the dosing period, the mean plasma concentration is about 22-970 pg/ml; at about 168 hours after the start of the dosing period (day 7 of the dosing period), the mean plasma concentration was about 19-841 pg/ml. In this example, the invention also relates to the use of a buprenorphine transdermal delivery device, when employed, which provides a mean relative release rate of from about 3 to about 86 μ g/hr, which rate is preferably maintained between the start of the administration period and about 72 hours from the start of the administration period; preferably, a mean relative release rate of about 0.3-9 μ g/hr is maintained from about 72 hours after the beginning of the dosing period to the end of the dosing period.

Any mode of administration may be employed to achieve the above plasma concentrations over a period of time. For example, buprenorphine may be administered transdermally, parenterally, sublingually, orally, buccally, rectally, and the like. Thus, with respect to the foregoing discussion, the plasma levels described for transdermal drug delivery devices are applicable to other such modes of administration. The oral bioavailability of buprenorphine is very low (estimated at 15%). For better control of buprenorphine plasma concentrations among those required by the inventive methods described herein, it is preferred that buprenorphine be administered by a transdermal delivery device or continuous infusion. Preferably, buprenorphine is administered by a means selected from the group consisting of transdermal, continuous infusion, and a combination of transdermal and continuous infusion. Optimal administration can be achieved by: the transdermal drug delivery device is applied to the skin of the patient and maintained in contact with the skin of the patient for at least 5 days.

In another preferred embodiment of the invention, buprenorphine is administered to a human patient such that the following mean plasma concentrations are obtained over a 72 hour dosing period: at about 6 hours after the start of the dosing period, the mean plasma concentration is about 1-28 pg/ml; at about 12 hours after the start of the dosing period, the mean plasma concentration is about 14-74 pg/ml; at about 24 hours after the start of the dosing period, the mean plasma concentration is about 30-161 pg/ml; at about 36 hours after the start of the dosing period, the mean plasma concentration is about 51-188 pg/ml; at about 48 hours after the start of the dosing period, the mean plasma concentration is about 62-246 pg/ml; at about 60 hours after the start of the dosing period, the mean plasma concentration is about 79-246 pg/ml; at about 72 hours after the start of the dosing period, the mean plasma concentration was about 85-263 pg/ml. Buprenorphine is then administered such that the mean plasma concentration is maintained between about 77 and 263pg/ml for at least 48 hours thereafter. Preferably, the mean plasma concentrations are maintained after 72 hours of the administration period as follows: at about 96 hours after the start of the dosing period, the mean plasma concentration is about 92-263 pg/ml; at about 120 hours after the start of the dosing period, the mean plasma concentration is about 94-263 pg/ml; at about 144 hours after the start of the dosing period, the mean plasma concentration is about 86-243 pg/ml; at about 168 hours after the start of the dosing period (day 7 of the dosing period), the mean plasma concentration was about 77-210 pg/ml. In this embodiment, when a transdermal delivery device is used, it is preferred to maintain a mean relative release rate of about 13-21 μ g/hr over the period of about 72 hours from the beginning of the administration period to the beginning of the administration period; the mean relative release rate is maintained at about 1-2 μ g/hr from 72 hours after the start of the dosing period to the end of the dosing period (e.g., 168 hours after the start of the 7 day dosing period).

In another preferred embodiment of the invention, buprenorphine is administered to a human patient such that the following mean plasma concentrations are obtained over a 72 hour dosing period: at about 6 hours after the start of the dosing period, the mean plasma concentration is about 0.3-7 pg/ml; at about 12 hours after the start of the dosing period, the mean plasma concentration is about 4-19 pg/ml; at about 24 hours after the start of the dosing period, the mean plasma concentration is about 7-40 pg/ml; at about 36 hours after the start of the dosing period, the mean plasma concentration is about 13-47 pg/ml; at about 48 hours after the start of the dosing period, the mean plasma concentration is about 16-62 pg/ml; at about 60 hours after the start of the dosing period, the mean plasma concentration is about 20-62 pg/ml; at about 72 hours after the start of the dosing period, the mean plasma concentration was about 20-66 pg/ml. Buprenorphine is then administered such that the mean plasma concentration is maintained between about 19 and 66pg/ml for at least 48 hours thereafter. Preferably, buprenorphine is administered such that the mean plasma concentrations are maintained as follows: at about 96 hours after the start of the dosing period, the mean plasma concentration is about 23-66 pg/ml; at about 120 hours after the start of the dosing period, the mean plasma concentration is about 23-66 pg/ml; at about 144 hours after the start of the dosing period, the mean plasma concentration is about 22-61 pg/ml; at about 168 hours after the start of the dosing period (day 7 of the dosing period), the mean plasma concentration was about 19-53 pg/ml. In this example, when a transdermal delivery device is used, the invention also relates to the use of a transdermal delivery device that provides a mean relative release rate of about 3 to about 5 μ g/hr over a period of time from the beginning of the administration period to about 72 hours after the beginning of the administration period; the mean relative release rate is maintained at about 0.3-0.6 μ g/hr from 72 hours after the start of the dosing period to the end of the dosing period (e.g., 168 hours after the start of the 7 day dosing period).

In another preferred embodiment of the invention, buprenorphine is administered to a human patient such that the following mean plasma concentrations are obtained over a 72 hour dosing period: at about 6 hours after the start of the dosing period, the mean plasma concentration is about 0.7-14 pg/ml; at about 12 hours after the start of the dosing period, the mean plasma concentration is about 7-37 pg/ml; at about 24 hours after the start of the dosing period, the mean plasma concentration is about 15-80 pg/ml; at about 36 hours after the start of the dosing period, the mean plasma concentration is about 25-94 pg/ml; at about 48 hours after the start of the dosing period, the mean plasma concentration is about 31-123 pg/ml; at about 60 hours after the start of the dosing period, the mean plasma concentration is about 40-123 pg/ml; at about 72 hours after the start of the dosing period, the mean plasma concentration was about 42-132 pg/ml. Buprenorphine is then administered such that the mean plasma concentration is maintained between about 38 and 132pg/ml for at least 48 hours thereafter. Preferably, further buprenorphine is administered such that the mean plasma concentrations are maintained as follows: at about 96 hours after the start of the dosing period, the mean plasma concentration is about 46-132 pg/ml; at about 120 hours after the start of the dosing period, the mean plasma concentration is about 47-132 pg/ml; at about 144 hours after the start of the dosing period, the mean plasma concentration is about 43-121 pg/ml; at about 168 hours after the start of the dosing period (day 7 of the dosing period), the mean plasma concentration was about 38-105 pg/ml. In this example, when a transdermal delivery device is used, the invention also relates to the use of a transdermal delivery device that provides a mean relative release rate of about 6 to about 11 μ g/hr over a period of time from the beginning of the administration period to about 72 hours after the beginning of the administration period; the mean relative release rate is maintained at about 0.7-1 μ g/hr from 72 hours after the start of the dosing period to the end of the dosing period (e.g., 168 hours after the start of the 7 day dosing period).

In another preferred embodiment of the invention, buprenorphine is administered to a human patient such that the following mean plasma concentrations are obtained over a 72 hour dosing period: at about 6 hours after the start of the dosing period, the mean plasma concentration is about 3-57 pg/ml; at about 12 hours after the start of the dosing period, the mean plasma concentration is about 28-148 pg/ml; at about 24 hours after the start of the dosing period, the mean plasma concentration is about 59-322 pg/ml; at about 36 hours after the start of the administration period, the mean plasma concentration was about 102-377 pg/ml; at about 48 hours after the start of the administration period, the mean plasma concentration was about 124-492 pg/ml; at about 60 hours after the start of the administration period, the mean plasma concentration was about 159-492 pg/ml; at about 72 hours after the start of the administration period, the mean plasma concentration was about 169-526 pg/ml. Buprenorphine is then administered such that the mean plasma concentration is maintained between about 153 and 526pg/ml for at least 48 hours thereafter. Preferably, buprenorphine is administered such that the mean plasma concentrations are maintained as follows: at about 96 hours after the start of the administration period, the mean plasma concentration was about 184-; at about 120 hours after the start of the administration period, the mean plasma concentration was about 187-526 pg/ml; at about 144 hours after the start of the administration period, the mean plasma concentration was about 173-485 pg/ml; at about 168 hours after the start of the dosing period (day 7 of the dosing period), the mean plasma concentration was about 153-420 pg/ml. In this example, when a transdermal delivery device is used, the invention also relates to the use of a transdermal delivery device that provides a mean relative release rate of from about 26 to about 43 μ g/hr over a period of time from the beginning of the administration period to about 72 hours after the beginning of the administration period; the mean relative release rate is maintained at about 2-4 μ g/hr from 72 hours after the start of the dosing period to the end of the dosing period (e.g., 168 hours after the start of the 7 day dosing period).

In another preferred embodiment of the invention, buprenorphine is administered to a human patient such that the following mean plasma concentrations are obtained over a 72 hour dosing period: at about 6 hours after the start of the dosing period, the mean plasma concentration is about 4-85 pg/ml; at about 12 hours after the start of the dosing period, the mean plasma concentration is about 42-222 pg/ml; at about 24 hours after the start of the dosing period, the mean plasma concentration is about 89-483 pg/ml; at about 36 hours after the start of the administration period, the mean plasma concentration was about 152-565 pg/ml; at about 48 hours after the start of the administration period, the mean plasma concentration was about 186-738 pg/ml; at about 60 hours after the start of the administration period, the mean plasma concentration was about 238-738 pg/ml; at about 72 hours after the start of the administration period, the mean plasma concentration was about 254-789 pg/ml. Buprenorphine is then administered such that the mean plasma concentration is maintained between about 230 and 789pg/ml for at least 48 hours thereafter. Preferably, buprenorphine is administered such that the mean plasma concentrations are maintained as follows: at about 96 hours after the start of the administration period, the mean plasma concentration was about 276-789 pg/ml; at about 120 hours after the start of the administration period, the mean plasma concentration was about 281-789 pg/ml; at about 144 hours after the start of the administration period, the mean plasma concentration was about 259-727 pg/ml; at about 168 hours after the start of the administration period (day 7 of the administration period), the mean plasma concentration was about 230-630 pg/ml. In this example, when a transdermal delivery device is used, the invention also relates to the use of a transdermal delivery device that provides a mean relative release rate of about 38 to about 64 μ g/hr over a period of time from the beginning of the administration period to about 72 hours after the beginning of the administration period; the mean relative release rate is maintained at about 4-7 μ g/hr from 72 hours after the start of the dosing period to the end of the dosing period (e.g., 168 hours after the start of the 7 day dosing period).

In another preferred embodiment of the invention, buprenorphine is administered to a human patient such that the following mean plasma concentrations are obtained over a 72 hour dosing period: at about 6 hours after the start of the dosing period, the mean plasma concentration is about 5-113 pg/ml; at about 12 hours after the start of the dosing period, the mean plasma concentration is about 55-296 pg/ml; at about 24 hours after the start of the administration period, the mean plasma concentration was about 118-644 pg/ml; at about 36 hours after the start of the dosing period, the mean plasma concentration was about 203-753 pg/ml; at about 48 hours after the start of the administration period, the mean plasma concentration was about 247-; at about 60 hours after the start of the administration period, the mean plasma concentration was about 317-984 pg/ml; at about 72 hours after the start of the administration period, the mean plasma concentration was about 339-1052 pg/ml. Buprenorphine is then administered such that the mean plasma concentration is maintained between about 306 and 1052pg/ml for at least 48 hours thereafter. Preferably, buprenorphine is administered such that the mean plasma concentrations are maintained as follows: at about 96 hours after the start of the administration period, the mean plasma concentration was about 369-1052 pg/ml; at about 120 hours after the start of the administration period, the mean plasma concentration was about 374-1052 pg/ml; at about 144 hours after the start of the administration period, the mean plasma concentration was about 346-970 pg/ml; at about 168 hours after the start of the dosing period (day 7 of the dosing period), the mean plasma concentration was about 306-841 pg/ml. In this example, when a transdermal delivery device is used, the invention also relates to the use of a transdermal delivery device that provides a mean relative release rate of from about 51 μ g/hr to about 86 μ g/hr over a period of time from the beginning of the administration period to about 72 hours after the beginning of the administration period; the mean relative release rate is maintained at about 5-9 μ g/hr from 72 hours after the start of the dosing period to the end of the dosing period (e.g., 168 hours after the start of the 7 day dosing period).

In another example of the present invention, a method comprises: buprenorphine is administered transdermally to human patients at different relative release rates, substantially first order release during the first 3 days of the dosing period, and zero order release during an additional at least 2 days of the dosing period, such that the average relative release rates obtained during the dosing period are as follows: (ii) a mean relative release rate of about 3-86 μ g/hr from the beginning of the dosing period to about 72 hours after the beginning of the dosing period; the mean relative release rate is about 0.3-9 μ g/hr from about 72 hours after the beginning of the dosing period to the end of the dosing period (e.g., 168 hours after the beginning of the 7 day dosing period).

In a preferred embodiment, the mean relative release rates obtained during the administration period are as follows: (ii) a mean relative release rate of about 3-5 μ g/hr from the beginning of the dosing period to about 72 hours after the beginning of the dosing period; the mean relative release rate is about 0.3-0.6 μ g/hr from about 72 hours after the start of the dosing period to the end of the dosing period (e.g., 168 hours after the start of the 7 day dosing period).

In another preferred example, the mean relative release rates obtained during the administration period are as follows: the mean relative release rate is about 6-11 μ g/hr from the beginning of the dosing period to about 72 hours after the beginning of the dosing period; the mean relative release rate is about 0.7-1 μ g/hr from about 72 hours after the beginning of the dosing period to the end of the dosing period (e.g., 168 hours after the beginning of the 7 day dosing period).

In another preferred example, the mean relative release rates obtained during the administration period are as follows: the mean relative release rate is about 13-2l μ g/hr from the beginning of the dosing period to about 72 hours after the beginning of the dosing period; the mean relative release rate is about 1-2 μ g/hr from about 72 hours after the beginning of the dosing period to the end of the dosing period (e.g., 168 hours after the beginning of the 7 day dosing period).

In another preferred example, the mean relative release rates obtained during the administration period are as follows: (ii) a mean relative release rate of about 26-43 μ g/hr from the beginning of the dosing period to about 72 hours after the beginning of the dosing period; the mean relative release rate is about 3-4 μ g/hr from about 72 hours after the beginning of the dosing period to the end of the dosing period (e.g., 168 hours after the beginning of the 7 day dosing period).

In another preferred example, the mean relative release rates obtained during the administration period are as follows: (ii) a mean relative release rate of about 39-63 μ g/hr from the beginning of the dosing period to about 72 hours after the beginning of the dosing period; the mean relative release rate is about 4-7 μ g/hr from about 72 hours after the beginning of the dosing period to the end of the dosing period (e.g., 168 hours after the beginning of the 7 day dosing period).

In another preferred example, the mean relative release rates obtained during the administration period are as follows: (ii) a mean relative release rate of about 51-86 μ g/hr from the beginning of the dosing period to about 72 hours after the beginning of the dosing period; the mean relative release rate is about 5-9 μ g/hr from about 72 hours after the beginning of the dosing period to the end of the dosing period (e.g., 168 hours after the beginning of the 7 day dosing period).

The methods of the present invention may be practiced with any suitable administration of buprenorphine known to those skilled in the art. However, some modes of administration are more practical than others. Preferred modes of administration are by continuous infusion, through the oral mucosa, or most preferably transdermal.

In the example of the invention described herein where plasma concentrations are achieved by intravenous infusion, the time-varying plasma concentration pattern seen in the present invention can be achieved with parenteral forms of injection (e.g., buprenorphine hydrochloride appropriately diluted in intravenous infusion). The infusion rate can be controlled with a programmed infusion pump to provide the desired plasma profile.

In a preferred embodiment of the invention, the buprenorphine is administered transdermally. Transdermal delivery of active agents is measured in terms of "relative release rate" or "flux" (i.e., the rate at which the active agent penetrates through the skin of the individual). Skin flux is typically determined according to the following equation:

dM/dt＝J＝P*C

where J is the skin flux, P is the permeability coefficient, and C is the concentration gradient across the membrane, assuming the same concentration as the donor. M represents the cumulative amount of drug entering the bloodstream. The variables dM and dt represent the change in cumulative amount of drug entering the bloodstream and the change in time, respectively.

It is well known in the art of transdermal drug delivery devices that in order to maintain a desired flux rate during a desired period of administration, it is necessary to include in the transdermal drug delivery device an excess amount of active agent that is significantly greater than the amount delivered to the patient over the desired period of time. For example, to maintain a desired flux rate for a three day period, it is believed that a significantly higher amount of active agent than the 100% three day dose would need to be included in a transdermal delivery device. This excess is necessary to create a concentration gradient with which the active agent migrates through the layers of the transdermal delivery device to the desired site on the skin of the patient. The remainder of the active agent remains in the transdermal delivery device. Only the portion of the active agent present in the transdermal delivery device will be absorbed by the skin. The total amount of active agent absorbed into the patient's bloodstream is less than the total amount provided. The amount of excess included in the transdermal delivery device depends on these and other factors known to the skilled artisan.

Surprisingly, it has been found that pain can be treated according to the invention by: a transdermal delivery device is provided containing sufficient opioid (e.g., buprenorphine) to provide the desired relative release rate for 3 days and to retain the transdermal dosage form on the skin for a period of about 5 to 8 days following a single administration (patch) of the dosage form to maintain flux, effective plasma levels, and analgesia for a longer period of time. Preferably, the desired flux is maintained for at least about 5 days (preferably at least about 8 days) after application of the transdermal delivery device. If the transdermal delivery device is removed 3 days after administration, there is no analgesia for a short period of time after removal (the analgesia for the retention time is provided by, for example, the amount of drug in the skin depot at the site of application of the transdermal delivery device). Surprisingly, however, if the transdermal delivery device is maintained in contact with the skin for about 5 to 8 days, analgesia will be maintained over an extended period of contact, but the patient will continue to experience analgesia. In other words, the inclusion of such an excess of buprenorphine would provide an analgesic effect of at least twice the expected 3-day dosing period.

The methods of the present invention may be used with any type of transdermal drug delivery device as long as the desired pharmacokinetic and pharmacodynamic response is obtained over a period of at least 3 days (e.g., about 5 to 8 days). Preferred transdermal drug delivery devices include, for example: transdermal patches, transdermal plasters, transdermal disks (discs), iontophoretic transdermal devices, etc.

For embodiments of the invention in which buprenorphine is delivered by a transdermal delivery device, it is contemplated, for example, that the transdermal delivery device contains about 68 to 95% buprenorphine at the end of the administration period.

For embodiments of the present invention in which buprenorphine is delivered by a transdermal delivery device, Tmax is expected to occur during a period of about 3 to 5 days after application of the transdermal delivery device.

The transdermal drug delivery device used in the present invention preferably comprises a buprenorphine-impermeable backing layer made of a pharmaceutically acceptable material. The backing layer preferably acts as a protective shell for the active agent (e.g., buprenorphine) and also provides a support function. Examples of materials suitable for preparing the backing layer are films of high and low density polyethylene, polypropylene, polyvinyl chloride, polyurethane, polyester (e.g. polyethylene phthalate), metal foils, metal foil laminates of these suitable polymer films, textiles if the drug storage layer (reservoir) component is not permeable to the textile due to its physical properties etc. Preferably, the material used for the backing layer is a laminate of these polymer films and a metal foil, such as aluminum foil. The backing layer may have a suitable thickness to provide the desired protective and support functions. Suitable thicknesses are about 10 to 200 microns. The materials and thicknesses required will be apparent to those skilled in the art.

In certain preferred embodiments, the transdermal drug delivery devices used in the present invention comprise a polymeric matrix layer. The polymers used to form the biologically acceptable polymer matrix are generally those that form a thin wall or coating that allows the drug to pass through at a controlled rate. A non-limiting list of typical materials included in the polymer matrix includes: polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene vinyl acetate copolymers, silicones, rubbers, rubber-like synthetic homo-, co-or block polymers, polyacrylates and copolymers thereof, polyurethanes, polyisobutylene, chlorinated polyethylene, polyvinyl chloride, vinyl chloride-vinyl acetate copolymers, polymethacrylate polymers (hydrogels), polyvinylidene chloride, polyethylene terephthalate, ethylene-vinyl alcohol copolymers, ethylene-vinyl oxyethanol copolymers, polysiloxanes including silicone copolymers (e.g., polysiloxane-polymethacrylate copolymers), cellulosic polymers (e.g., ethyl cellulose and cellulose esters), polycarbonates, polytetrafluoroethylene, and mixtures thereof.

Preferred materials for inclusion in the polymeric matrix layer are silicone elastomers (e.g., silicone polymers) having the general structure polydimethylsiloxane. Preferred siloxane polymers are crosslinked and pharmaceutically acceptable. Other preferred materials for inclusion in the polymer matrix layer include: siloxane polymers, which are crosslinkable copolymers, have dimethyl and/or dimethylvinylsiloxane units that can be crosslinked with a suitable peroxide catalyst. Also preferred are block copolymers based on styrene and 1, 3-dienes (in particular linear styrene-isoprene block copolymers or styrene-butadiene block copolymers), polyisobutenes, polymers based on acrylates and/or methacrylates.

The polymeric matrix layer may optionally include a pharmaceutically acceptable cross-linking agent. Suitable crosslinking agents include, for example, tetrapropoxysilane.

The preferred transdermal delivery device for use in the method of the present invention comprises an adhesive layer which adheres the dosage form (i.e., the transdermal delivery device) to the skin of the patient for the desired administration period (e.g., about 5 to 8 days). If the adhesive layer of the dosage form does not provide adhesion for the desired period of time, the dosage form may be attached to the skin of the patient, for example, with an adhesive tape (e.g., medical tape) to hold the dosage form in contact with the skin. Whether the adherence of the dosage form to the patient's skin is achieved solely by the dosage form adhesive layer or by a surrounding adhesive source, such as medical tape, is not critical for the purposes of the present invention, so long as the dosage form is adhered to the patient's skin for the necessary administration time.

The adhesive layer preferably comprises a pharmaceutically compatible adhesive known in the art for use with the dosage form, preferably a hypoallergenic material such as polyacrylic adhesive polymers, acrylate copolymers (e.g., polyacrylates), and polyisobutylene adhesive polymers. In other preferred embodiments of the invention, the adhesive is a pressure sensitive contact adhesive, which is preferably a hypoallergenic material.

The transdermal drug delivery devices employed in the present invention may optionally include a permeation enhancer. Permeation enhancers are compounds that promote the penetration and/or absorption of buprenorphine into the bloodstream of a patient. A non-limiting list of penetration enhancers includes polyethylene glycol, surfactants, and the like.

Additionally, after the dosage form (dosage form) is applied to the desired site on the patient, the dosage form may be encapsulated, for example, with an encapsulating tape to enhance penetration of the buprenorphine. Penetration may also be enhanced by removing hair at the application site (e.g., by cutting, scraping, or with depilatories). Another penetration enhancer is heat. It is believed that the heat enhancement means can be induced in a variety of ways, one of which is the application of a form of radiant heat (e.g., infrared lamps) to the application site after the transdermal dosage form is applied. Other means of enhancing buprenorphine penetration, such as iontophoresis, are also included within the scope of the present invention.

A preferred transdermal delivery device for use with the present invention comprises: an impermeable backing layer made of, for example, polyester; an adhesive layer made of, for example, polyacrylate; and a base containing buprenorphine and other desired pharmaceutical adjuvants such as emollients, penetration enhancers, viscosity agents, and the like.

The active agent may be contained in the drug reservoir layer, drug matrix or drug/adhesive layer of the device. Preferably, the active agent is buprenorphine or a pharmaceutically acceptable salt thereof.

Certain preferred transdermal drug delivery devices also include an emollient. Suitable softeners include higher alcohols (e.g. lauryl alcohol, undecyl alcohol, octanol), carboxylic acid esters, wherein the alcohol component may also be polyethoxylated alcohols, diesters of dicarboxylic acids (e.g. di-n-butyl adipate) and triglycerides (especially medium-chain triglycerides of caprylic/capric acid or coconut oil, have proven particularly suitable). Other examples of suitable emollients are polyols such as levulinic acid, caprylic acid (coco acrylic acid) glycerol and 1, 2-propanediol (which may also be esterified with polyethylene glycol).

A solvent for buprenorphine may also be included in the transdermal delivery device of the present invention. Preferably, the solvent sufficiently dissolves the buprenorphine to avoid complete salt formation. A non-limiting list of suitable solvents includes those solvents having at least one acidic group. Particularly suitable solvents are monoesters of dicarboxylic acids, for example monomethyl glutarate and monomethyl adipate.

Other pharmaceutically acceptable compounds that may be included in the drug storage layer or matrix include: solvents, such as alcohols (e.g., isopropanol); a penetration enhancer as described above; and viscosity agents such as cellulose derivatives, natural or synthetic gums (e.g., guar gum), and the like.

In a preferred embodiment, the transdermal delivery device includes a removable protective layer. The removable protective layer is removed prior to application and consists of the material used to produce the backing layer described above, provided it is removable by, for example, a silicone treatment. Other removable protective layers are for example polytetrafluoroethylene, treated paper, allophane, polyvinyl chloride, etc. The removable protective layer is typically in contact with the adhesive layer and provides a convenient way to maintain the integrity of the adhesive layer until it is needed for application.

The composition of the transdermal drug delivery device employed in the present invention and the type of system (device) used are not considered critical to the present invention, so long as the device is capable of sustained delivery of the active agent (e.g., buprenorphine) at the desired flux rate and/or the desired delivery rate of the transdermal dosage form for the desired time.

Certain preferred transdermal drug delivery devices for use with the present invention are described in U.S. Pat. No.5,240,711(Hille et al; assigned to LTS Lohmann Therapie-Systeme GmbH & Co.), which is incorporated herein by reference. These buprenorphine transdermal delivery devices may be laminated composites having an impermeable backing layer containing buprenorphine and optionally a combination of a pressure sensitive adhesive and a permeation enhancer. According to the' 711 patent, preferred transdermal dosage forms include: (i) a buprenorphine-impermeable polyester backing layer; (ii) a polyacrylate adhesive layer; (iii) a separate polyester layer; and (iv) a matrix containing buprenorphine, a buprenorphine solvent, a softening agent, and a polyacrylate binder. Buprenorphine solvent may or may not be present in the final formulation. The transdermal drug delivery device described herein comprises: an active substance impermeable backing layer, a pressure sensitive adhesive drug-containing layer and optionally a removable protective layer. Preferably, the drug storage layer comprises from about 10% to about 95% by weight of the polymer, from about 0.1% to about 40% by weight of the softening agent, and from about 0.1% to about 30% by weight of buprenorphine. The solvent for the buprenorphine base, or a pharmaceutically acceptable salt thereof, may comprise from about 0.1% to about 30% by weight.

In a preferred example, a transdermal drug delivery device is prepared according to example 1 attached hereto. In this example, a transdermal drug delivery device is prepared according to the disclosure in International patent application No. WO96/19975 (Hille et al; assigned to LTSLohman therapy-Systeme GMBH), which is incorporated herein by reference. In this device, the buprenorphine transdermal delivery device contains an auxiliary substance that promotes resorption. The auxiliary substances that promote reabsorption form supercooled substances. The delivery device contains 10% buprenorphine base (base), 10-15% acid (e.g., levulinic acid), about 10% emollient (e.g., oleoyl oleate), 55-70% polyacrylate, and 0-10% polyvinylpyrrolidone (PVP).

In the present example where plasma concentrations of buprenorphine described herein were obtained with a transdermal delivery device made in accordance with WO96/19975, for example, nominal buprenorphine delivery rates for these patches would be expected to be in the range of, for example, 12.5-100 μ g/hour. In certain preferred embodiments, to achieve a nominal delivery rate of 12.5 μ g/hr, the total buprenorphine content in the transdermal patch is about 5mg, and the active surface area is about 6.25cm²The patch size may be, for example, about 19.4cm². In certain preferred embodiments, the total buprenorphine content of the transdermal patch is about 10mg and the active surface area is about 12.5cm in order to achieve a nominal delivery rate of 25 μ g/hr²The patch size may be, for example, 30.6cm². In certain preferred embodiments, the total buprenorphine content of the transdermal patch is about 20mg and the active surface area is about 25cm in order to achieve a nominal delivery rate of 50 μ g/hr²The patch size may be, for example, 51.8cm². In certain preferred embodiments, the total buprenorphine content of the transdermal patch is about 30mg and the active surface area is about 37.5cm in order to achieve a nominal delivery rate of 75 μ g/hr²The patch size may be, for example, 69.8cm². In certain preferred embodiments, the total buprenorphine content of the transdermal patch is about 40mg and the active surface area is about 50cm in order to achieve a nominal delivery rate of 100 μ g/hr²The patch size may be, for example, 87.8cm²。

In accordance with the inventive method, the above-described transdermal delivery device has been designed to adhere to the patient for only 3 days, and is expected to deliver an analgesic effective dose of buprenorphine for only about 3 days. In contrast, in accordance with the present invention, the transdermal device is maintained in contact with the patient's skin for an extended period of time (e.g., about 5 to 8 days) without changing the formulation of the transdermal device itself. It has been surprisingly found that the analgesic effect can be maintained for an extended period of time (which exceeds the useful life of the transdermal formulation design).

In other examples, the buprenorphine transdermal delivery device may be a plaster such as that described in U.S. patent No.5,225,199 (to Hidaka et al), which is incorporated herein by reference. The plaster comprises a film layer and an adhesive layer, the film layer comprising a polyester film, the film having a thickness of about 0.5 to 4.9 μm in two directions intersecting at substantially right angles, a strength of about 8 to 85g/mm, an elongation of 30 to 150% in the two directions intersecting at substantially right angles, and an elongation ratio of A to B of about 1.0 to 5.0, wherein A and B represent data in the two directions intersecting at substantially right angles, and A is greater than B, wherein the polyester film comprises about 0.01 to 1.0% by weight (based on the total weight of the polyester film) of solid fine particles having an average particle diameter of about 0.001 to 3.0 μm; the adhesive layer is composed of an adhesive containing a transdermally absorbable drug; wherein an adhesive is laminated on a surface of the film layer having a thickness of about 2 to 60 μm. The average particle diameter is not substantially more than 1.5 times the thickness of the polyester film.

Transdermal drug delivery devices for use in the present invention may also be prepared according to U.S. patent No.5,069,909(Sharma et al), which is incorporated herein by reference. This patent describes a laminated complex for transdermal administration of buprenorphine to treat pain. The composite includes an impermeable backing layer that provides a protective covering for the composite, which may be made of an elastomeric polymer such as polyurethane, polyetheramide, or copolyester, and may have a thickness of about 15 to 250 microns. The composite also includes a reservoir layer comprising 1-12% by weight buprenorphine (base or hydrochloride salt) and a pressure sensitive adhesive, for example a polyisobutylene, or a silicone adhesive such as a silicone rubber, or an acrylate adhesive, and 2-35% of a penetration enhancer comprising propylene glycol monolaurate in combination with capric acid or oleic acid. The amounts of buprenorphine and penetration enhancer are sufficient to provide buprenorphine at about 1 to 100 μ g/cm²The speed per hour was through the skin.

Transdermal drug delivery devices for use in the present invention may also be prepared according to U.S. patent No.4,806,341(Chien et al), which is incorporated herein by reference. This patent describes a transdermal morphinan narcotic analgesic or antagonist (including buprenorphine) pharmaceutical polymer matrix dosage unit (matrix dosage unit) having a substantially buprenorphine impermeable backing layer and a wafer layer of polymer matrix adhered to the backing layer and having an effective dose of buprenorphine microdispersed therein. The polymer matrix may be a silicon polymer or copolymer, such as a methyl siloxane polymer or copolymer, or a methyl vinyl siloxane polymer or copolymer. Preferably, the polymeric matrix layer has dispersed therein a skin penetration enhancer (e.g., isopropyl myristate, azone or a combination of ethyl octanoate and octanol).

The transdermal drug delivery devices useful in the present invention may also be those described in U.S. Pat. No.5,026,556(Drust et al), which is incorporated herein by reference. Wherein the composition for transdermal delivery of buprenorphine comprises buprenorphine in a carrier selected from the group consisting of C₃-C₄Diol, C₃-C₆A polar solvent material selected from the group consisting of triols and mixtures thereof, and a polar lipid material selected from the group consisting of fatty alcohol esters, fatty acid esters and mixtures thereof, wherein the solvent material to lipid material weight ratio of polar solvent material to lipid material is from 60: 40 to about 99: 1.

The transdermal drug delivery devices useful in the present invention may also be those described in U.S. Pat. No.4,588,580(Gale et al), which is incorporated herein by reference. The device comprises a drug reservoir layer adjacent to the skin having a substance release surface area of about 5-100cm²And contains from 0.1 to 50% by weight of buprenorphine in a skin-permeable form. The drug reservoir layer contains a hydrogel comprising up to about 47-95% ethanol, 1-10% gelling agent, 0.1-10% buprenorphine, and a release rate control device disposed in the inflow path of the drug into the skin that limits the flux of buprenorphine from the device through the skin. The release rate controlling means, which makes the buprenorphine more permeable than ethanol, may be, for example, Low Density Polyethylene (LDPE), ethylene-vinyl acetate (EVA) copolymer, heat-sealable polyEsters, and elastomeric polyester block copolymers (e.g., of DuPont)). The device is said to provide an administration rate of about 10-300 mug/hour. In order to carry out the method of the present invention, it is expected that each of the transdermal delivery devices described herein (other than the devices listed in example 1 appended hereto) will require less control. Such modifications are well within the ability of those skilled in the art of formulating such transdermal delivery devices.

The present invention may also be practiced by utilizing a sustained oral mucus delivery device. This device delivers "j.controlled Release" for continuous oromucosal delivery in volunteers "of McQuim, r.l. et al; (34)1995(243- & 250). Wherein buprenorphine free base (8%), carbopol 934 (52%), polyisobutylene (35%) and polyisoprene (5%, w/w) were mixed uniformly using a two-roll mill, and then the mixture was pressed to an appropriate thickness to prepare an oral mucosal patch. A film backing (ethyl cellulose) was applied to the pressed side, and then circular disks (0.5 cm) were punched from the material²). The backing is included to delay drug release from one side of the disc and to prevent adhesion to the contralateral tissue. Each floppy disk was approximately 0.6mm thick and contained 2.9mg of buprenorphine. Subjects applied these patches for 12 hours. Gum and lip application were tested, but the gum site was considered to adhere better. After the initial appearance of serum buprenorphine (. gtoreq.25 pg/ml), the level generally increased relatively rapidly and continued until the patch was removed. Buprenorphine levels decreased rapidly after patch removal, with relatively low (but detectable) levels at 24 hours post-administration. It is estimated that 0.42. + -. 0.18mg is delivered through the gum. From this discussion, it is apparent that an oral mucosal patch can be made that will provide the plasma concentrations considered desirable for the present invention.

When opioid analgesics are administered at high blood levels, the incidence of side effects (such as nausea, vomiting, or drowsiness) is generally expected to be significantly higher. The present invention has a lower incidence of side effects by maintaining a lower blood level of the drug during the 7 day administration period while maintaining effective analgesia. In contrast, when a new transdermal drug delivery device of the same intensity was applied every third day, the plasma concentration in the patient was found to be much higher in the same time period, and thus it is expected that the administration of a new transdermal device every 3 days would increase side effects.

Generally, there is a time "lag" between drug efficacy and the time course of opioid plasma concentration levels when opioid analgesics are administered. Typically, peak plasma level concentrations are usually achieved before the maximum drug therapeutic effect or side effect response is manifested. It has surprisingly been found that the method of the invention provides an "opposite hysteresis", i.e. an increase in plasma concentration after the appearance and rise of certain pharmacodynamic behaviors and side effects.

It is to be understood that for purposes of this invention, the following terms have the following meanings:

the term "effective analgesia" for the purposes of the present invention means a satisfactory reduction or elimination of pain, with tolerable levels of side effects (as determined by human patients).

The term "effectively treating pain" means, for the purposes of the present invention, the objective assessment by a physician of the response of a human patient to an analgesic treatment (pain experienced versus side effects) and the subjective assessment of the treatment by the patient treated therewith. It will be appreciated by those skilled in the art that effective analgesia will vary depending on a number of factors, including individual patient variability.

The term "mean" used in conjunction with the terms "plasma concentration", "release rate", "maximum plasma concentration" and "minimum plasma concentration" is meant to encompass multiple administrations (for a single dose or steady state condition) of an individual patient as well as a group of patients.

For the present example of a buprenorphine medicament being a transdermal delivery device, for the purposes of the present invention, the buprenorphine transdermal delivery device is removed from the patient's skin and the same or a different transdermal delivery device is subsequently reapplied before the plasma levels of buprenorphine fall below the minimum effective concentration, which is also encompassed by the scope of the appended claims. For example, it is contemplated that the buprenorphine transdermal delivery device may be removed from the patient while bathing for anywhere from a few minutes to a few hours. Indeed, it has been demonstrated herein that once an effective buprenorphine plasma concentration is achieved transdermally, a buprenorphine plasma level effective to relieve pain (e.g., 24 hours) is maintained in the patient even if the transdermal delivery device is removed. It is hypothesized that a dermal drug reservoir is created by the use of transdermal buprenorphine delivery devices, including those demonstrated in the examples. When the transdermal delivery device is reapplied before the skin reservoir is completely depleted, it is preferred that the transdermal delivery device be reapplied to the same location on the patient's skin to replenish the skin reservoir (i.e., depot). The plasma concentration profile obtained during, for example, 7 days of administration may be interpreted as a small amount of buprenorphine still being released from the transdermal delivery device (re-replenishing the skin reservoir) from day 4 to day 7 after the initial application of the device to the patient's skin, as well as a sustained release and sustained delivery of buprenorphine to the skin reservoir. The balance between sustained release of the device and sustained delivery of the skin reservoir (among other factors such as distribution) determines the plasma concentration seen in a particular individual. This also explains why buprenorphine plasma concentrations do not drop as abruptly on days 4 to 7 as when the removal device is not in contact with the patient's skin. The skin reservoir hypothesis presented herein also explains why the elimination curve after patch removal is longer than would be expected by one skilled in the art for intravenous administration of the drug buprenorphine. The skin reservoir is assumed to be suitable for explanation only and is not intended to limit the claims in any way.

The term "breakthrough pain" refers to the pain experienced by a patient despite the administration of a generally effective amount of an opioid analgesic (e.g., buprenorphine) to the patient.

The term "rescue" refers to the amount of analgesic agent administered to a patient experiencing breakthrough pain.

The term "primary" pharmacokinetics is defined as an increased plasma concentration over a specified period. The amount of drug released from the suspension matrix according to first order kinetics can be defined as follows:

amount of release per unit area(first order kinetics)

D_effApparent diffusion coefficient

C_oInitial drug concentration in transdermal drug delivery devices

C_sSaturation concentration

t is time

Suppose that: complete penetration; diffusion of the dissolved drug is rate-controlled; thus, it is possible to provide

Solution-based drug release according to first order kinetics can be defined as follows:

amount of release per unit area(first order kinetics)

Suppose that: complete penetration; diffusion of the dissolved drug is rate-controlled; m_t≤0.4M_oThus, therefore, it is

The term "zero order" pharmacokinetics means that the amount of drug released from the buprenorphine formulation substantially maintains plasma concentrations at relatively constant levels. For the purposes of the present invention, a relatively constant plasma concentration is defined as a concentration that does not decrease by more than about 30% over a 48 hour period.

The drug release of the membrane controlled device can be defined as follows:

the amount of release per unit area Q is constant (zero order kinetics)

The term "average relative release rate" is based on the amount of drug released from a transdermal device through the skin and into the bloodstream of a human patient per unit time. The average relative release rate can be expressed, for example, as μ g drug/cm²In terms of hours. For example, a transdermal drug delivery device that delivers 1.2mg of buprenorphine in 72 hours is believed to have a relative release rate of 16.67 μ g/hour. For the purposes of this invention, it is understood that the relative release rate between any particular time points during a particular administration period may vary, and thus the term simply reflects the overall release rate during a particular administration period. For the purposes of the present invention, relative release rates should be considered synonymous with the term "flux rate".

For the purposes of the present invention, the term "sustained release" is defined as the rate at which the drug is released from the transdermal formulation at which the blood (e.g., plasma) concentration (level) is maintained within the therapeutic range (above the minimum effective analgesic concentration (i.e., MEAC)) but below toxic levels for about 3 days or more.

The term "steady state" refers to a plasma concentration profile of a given drug that substantially recurs from dose to dose.

For the purposes of the present invention, the term "minimum effective analgesic concentration" is defined as the minimum therapeutically effective plasma concentration of a drug at which the drug achieves at least some degree of pain relief in a given patient. It is well understood by those skilled in the medical arts that pain measurements are highly subjective and may vary greatly from patient to patient.

For the purposes of the present invention, the term "buprenorphine" shall include buprenorphine base, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers and esters thereof, and mixtures thereof.

For the purposes of the present invention, the term "overage" refers to the amount of buprenorphine contained in the transdermal delivery device that is not delivered to the patient. The excess is required to create a concentration gradient with which the active agent (e.g., buprenorphine) migrates through the transdermal layer to the desired site of the patient's skin.

Drawings

The following drawings are intended to depict examples of the invention and are not intended to limit the scope of the invention encompassed by the claims.

FIG. 1 is a graph of mean plasma concentration (pg/ml) versus time (days) for example 1;

FIG. 2 is a graph of pharmacodynamic variables versus time (days) in example 1;

FIG. 3 is a graph of plasma concentration (pg/ml) over time (hours) for comparative example A;

FIG. 4 is a graph of plasma concentration (pg/ml) over time (hours) in comparative example B (intravenous concentration divided by 100);

FIG. 5 is a graph of plasma concentration (pg/ml) over time (hours) for comparative example C;

FIG. 6 is a graph of pharmacodynamic variables versus time (hours) for comparative example A;

FIG. 7 is a graph of pharmacodynamic variables versus time (hours) for comparative example B;

FIG. 8 is a graph of pharmacodynamic variables versus time (hours) for comparative example C;

FIG. 9 is a graph of plasma concentration (pg/ml) over time (hours) for comparative example D;

FIG. 10 is a graph of plasma concentration (pg/ml) over time (hours) for comparative example E;

FIG. 11 is a graph of plasma concentration (pg/ml) over time (hours) for comparative example F;

FIG. 12 is a graph of pharmacodynamic variables versus time (hours) for comparative example D;

FIG. 13 is a graph of pharmacodynamic variables versus time (hours) for comparative example E; and

figure 14 is a graph of pharmacodynamic variables versus time (hours) for comparative example F.

Description of the preferred embodiments

The following examples describe various aspects of the invention. These examples are not to be considered as limiting the claims in any way.

Example 1

A pharmacokinetic/pharmacodynamic study was performed in 24 healthy human patients for 7 days. Subjects included approximately equal numbers of males and females. In this study, buprenorphine was administered via a transdermal patch as described in WO 96/19975.

The transdermal patch used in example 1 was prepared according to the disclosure of WO96/19975 as follows: 1.139 g of a 47.83% by weight polyacrylate solution (acrylic copolymer containing 2-ethylhexyl acrylate, vinyl acetate, acrylic acid self-reticulate (selfnet) with the solvent ethyl acetate: heptane: isopropanol: toluene: acetylacetonate in a ratio of 37: 26: 4: 1), 100 g of levulinic acid, 150 g of oleoyl oleic acid (oleyloleate), 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate and 100 g of buprenorphine base were mixed. The mixture was stirred for about 2 hours and then visually inspected to determine if all solid material had dissolved. Evaporation losses were controlled by re-weighing and, if necessary, made up with ethyl acetate. Then, when the weight per unit surface of the dried paste was 80 g/m²The mixture was then placed on a transparent polyester foil 420mm wide. The polyester foil acts as a protective layer and it can be redissolved by a silicone treatment. The solvent was removed by hot air drying to form wet channels (led over a moist Lane). With this warming treatment, not only the solvent is evaporated, but also levulinic acid is melted. Then, the seal was covered with 15 μ ab. polyester foilAnd (3) a membrane. Cut out about 16cm with a suitable cutting tool²Removing the edges that have remained between the individual devices.

Example 1 the formulation used was substantially as described in example 3 of WO96/19975, prepared according to the method of example 1, comprising 10% buprenorphine, 10% levulinic acid, 10% polyvinylpyrrolidone, 10% oleoyl oleic acid and 60% polyacrylate.

To achieve the nominal delivery rate of 25 mug/hr expected from the formulation of example 1, a total of about 10mg buprenorphine is included in the transdermal patch with an active surface area of about 12.5cm²The patch size is, for example, about 30.6cm²。

The dosing regimen was a patch containing 10mg buprenorphine base per patch reservoir applied to the skin of the subject and maintained in contact with the skin for 7 days.

At approximately 8:00 on the first day, the adhesive patch containing the agent to be tested was applied to the 5 th intercostal site of the right axillary midline. For patch application, the skin is washed with warm soapy water, then rinsed with clean water and left to dry in the air. The skin is not rubbed during washing. The application site has relatively few hairs. The hair is not cut or shaved off. The patch was removed at approximately 8:00 on day 8. After removal of the patch, the patch site is not washed or rubbed until the end of the last blood collection during the treatment period. Each patch was placed unfolded on its release liner and the patch/release liner unit was placed in the correct bag and then sent to the bioanalytical laboratory to determine the residual amount of buprenorphine.

Blood sampling began on day 1(10 ml at each time point) and then continued for the following time: hour 1 (pre-dose) and fixed intervals during 7 days of dosing.

Skin observation at the patch site: the quality of the skin at the site of the actual reservoir of the patch was evaluated by the investigator/worker at 0 hours (prior to patch application) and 30 minutes after patch removal. The evaluation grades were as follows:

erythema: 0 ═ no visible red; 1-very pale red (just noticeable); 2-mild but distinct red; 3 ═ medium intensity red; 4 ═ severe erythema (deep red blotches of skin).

Edema: 0 ═ no visible reaction; 1-very mild edema (barely detectable); 2-mild edema (the corners of the area are evident due to the apparent bumps); moderate edema (bumps up to 1 mm in diameter); severe edema (bulge diameter greater than 1 mm, bulge beyond patch edge).

The following pharmacokinetic parameters were estimated: AUC_(0-Final)(pg. h/ml) -the area under the curve from time zero to time of final non-zero buprenorphine plasma concentration, calculated according to the linear trapezoidal method;

C_max(pg/ml) -the maximum plasma buprenorphine concentration observed during dosing; if C is present_maxAt a plurality of time points, T_maxIs defined as the first C_maxThe time point of (a); residual amount-the amount of buprenorphine remaining in the patch used (mg/patch).

Table 1 below lists a summary of buprenorphine plasma concentrations (expressed in picograms per milliliter, i.e., pg/ml):

¹hours after administration of a medicament (e.g., patch)

²Mean plasma concentration (pg/ml) of 24 test subjects

³Standard deviation of mean plasma concentration

⁴Coefficient of difference (%)

The mean plasma concentration values (concentration pg/ml vs. time (days)) are further shown in figure 1. As is evident from the pharmacokinetic results obtained in example 1, the mean plasma concentration steadily increased and peaked at about 3 days during the dosing period (e.g., about 72 hours after patch application) and then surprisingly remained relatively stable for the remainder of the dosing period (e.g., to about the 7 day time point, 168 hours after the start of the dosing period). Furthermore, it is evident from the buprenorphine plasma concentrations that there is first order kinetics during the first 72 hours of the dosing period and substantially zero order kinetics thereafter.

Table 2 below sets out a summary of the pharmacokinetic parameters obtained in example 1:

5 minutes before each blood draw, the following pharmacokinetic parameters were evaluated by: each patient is asked to answer several questions, with the patient placing the answers to the questions with vertical marks at the appropriate locations on a 100 millimeter visual analog scale ("VAS"), with "none" affixed to one end and "very much" affixed to the other end. The first question to ask the subject is "do you feel the effect of the drug? "after the patient marks his/her answer to the question on the VAS, an answer is obtained through the VAS as to whether the patient feels (i) nausea, (ii) dizziness, and (iii) drowsiness. The results are shown in Table 3. All pharmacokinetic parameters were summarized and tabulated. The pharmacokinetic and pharmacodynamic relationships were then modeled with a mixed effect (linear or non-linear). The results (VAS) for the pharmacodynamic parameters are shown in figure 2.

As can be seen from the results in table 3, only one case reported by the subjects during the administration had moderate side effects and no severe side effects. Furthermore, as can be seen from fig. 2, after day 3 of the dosing period, the degree of dizziness, nausea and drowsiness decreased significantly. The incidence of other side effects (such as headache, vomiting and constipation) is also low.

Table 4 provides a list of the measurements of the residual amount of drug in the patch removed from the subject after 7 days.

Comparative examples A to C

Three treatments and randomized, crossover studies were performed in normal volunteers. Treatments included comparative example a (buprenorphine transdermal delivery device alone); comparative example B (single intravenous buprenorphine dose) and comparative example C (3 consecutive applications of the buprenorphine transdermal delivery device used in comparative example a every 3 days). Wash-out periods of 10-14 days were spaced between the first days of administration (application) for each treatment. For buprenorphine transdermal delivery devices, cleaning was initiated upon removal of the third patch. Due to analytical chemistry considerations and different sampling times, the study was not analytically blind.

The buprenorphine transdermal delivery device (patch) used in comparative examples a and C contained 20mg of buprenorphine base, which was prepared according to example 1. The buprenorphine patches of comparative examples a and C are expected to provide approximately twice the dose and relative release rate of the buprenorphine patch of example 1. For comparative examples a and C, the patch is expected to release approximately 1.2mg buprenorphine per day, which is equivalent to 0.3mg given intravenously every 6 hours. With reference toBuprenorphine was injected intravenously (comparative example B) at 0.3 mg: (Injection 0.3mg/ml, [1 ml/tube ]])。

In comparative example a, a buprenorphine transdermal delivery device (single dose) was adhered to a relatively small area of hair at the 5 th rib site of the right thoracic axillary midline of a subject at about 8 am on day 1 and removed at about 8 am on day 4. For comparative example a (single dose buprenorphine transdermal delivery device), blood samples were taken as follows: day 1: 0 (adhesive buprenorphine transdermal delivery device), 2, 3, 4, 6, 8, 10, 12 and 16 hours; day 2: 0, 6 and 12 hours; day 3: 0, 12 hours; day 4: 0 (before removal), 0.25, 0.5, 0.75, 1, 2, 3, 6, 12 hours (after removal); day 5: 0, 12 hours; day 6: 0, 12 hours; day 7: at 0 hour.

For the intravenous buprenorphine injection of comparative example B, 0.3mg was infused into the right-hand contraelbow (anti) vein by an indwelling cannula at approximately 8 am on day 1. An intravenous blood sample of 0.3mg buprenorphine was collected as follows; day 1: 0, 1, 2, 3, 5, 10, 15, 20, 25, 30, 45 minutes and 1, 1.5, 2, 3, 4,5, 6, 10, 12, 24 hours; arterial blood samples (left radial artery) for the first 4 hours; intravenous blood samples from 2 hours post-dose to 24 hours post-dose. Therefore, arterial and venous blood samples were taken at 2, 3 and 4 hours post-dose.

For comparative example C, a buprenorphine transdermal delivery device (applied 3 consecutive times) was adhered to a relatively small area of hair at the 5 th rib site of the subject's right thoracic axillary midline at about 8 am on day 1 and removed at about 8 am on day 4. After removing the first patch at about 8 am on day 4, a second buprenorphine transdermal delivery device was placed 50 μ g/hr in close proximity to the first patch and removed at about 8 am on day 7. After removing the second patch at about 8 am on day 7, a third buprenorphine transdermal delivery device was placed 50 μ g/hr next to the second patch, but not in the same location as the first patch, and removed at 8 am on day 10. Blood samples of comparative example C (3 consecutive applications of the buprenorphine transdermal drug delivery device) were obtained as follows: the first day: 0, (adhesive buprenorphine transdermal delivery device), 2, 3, 4, 6, 8, 10, 12, and 16 hours; day 2: 0, 6 and 12 hours; day 3: 0, 12 hours; day 4: 0 (before patch removal) and 2, 3, 4, 6, 8, 10, 12, 16 hours (after second buprenorphine transdermal delivery device is adhered); day 5: 0, 6 and 12 hours; day 6: 0, 12 hours; day 7: 0, (before patch removal), and 2, 3, 4, 6, 8, 10, 12, 16 hours (after third buprenorphine transdermal delivery device is adhered); day 8:0, 6 and 12 hours; day 9: 0, 12 hours; day 10: 0 (before removal of the buprenorphine transdermal delivery device), and 0.25, 0.5, 0.75, 1, 2, 3, 6, 12 hours (after removal); starting the washing phase after removing the patch on day 10; day 11: 0, 12 hours; day 12: 0, 12 hours; and day 13: 0.

the pharmacokinetic variables determined for comparative examples a-C are as follows:

AUC_(0-Final): pg-hour/ml-area under the curve to the last observation calculated with linear trapezoidal method;

AUC_inf: pg-h/ml-calculating the area under the curve by a linear trapezoidal method;

C_max: pg/ml-maximum buprenorphine plasma concentration measured over a specified period;

T_max: time at the hourly-maximum buprenorphine plasma concentration measurement; when a plurality of time points have a maximum value, T_maxRefers to the first point in time having that value;

T_(1/2)elm: plasma half-life for buprenorphine clearance, defined as ln2/K_elmIn which K is_elmIs the first order apparent clearance constant. The clearance rate constant was obtained from the end slope of the plasma concentration time curve measured by regression analysis.

T_(1/2)abs: the absorption half-life of transdermal buprenorphine clearance, defined as ln2/K_absIn which K is_absIs the first order apparent absorption constant. Calculating the rate of absorption for only transdermal buprenorphine;

cl: ml/min or l/h-total clearance represents clearance of a hypothetical plasma volume of drug per unit time;

V_d: liter or liter/kg-the assumed volume of drug dispensed in vivo; and

absorption speed: microgram/hr-the rate at which buprenorphine enters systemic circulation.

Plasma concentration data were analyzed using standard non-compartmentalization (noncompartmental) and compartmentalization techniques to derive pharmacokinetic parameters. In addition, various methods of investigation are employed, including fitting intravenous data to pharmacokinetic models to determine which model best describes the data, and overlapping legal (deconstruction) analysis to determine the rate of absorption. Other parameters (e.g., clearance, volume of distribution, rate of absorption, amount of absorption, and bioavailability) are determined using standard non-compartmentalized or compartmentalized analysis or research methods. Intravenous data were also analyzed using compartmentalization model design methods.

A summary of buprenorphine plasma concentrations for comparative example a is provided in table 5 below:

a summary of buprenorphine plasma concentrations (pg/ml) per sampling time for comparative example C is provided in table 6 below:

a summary of the mean plasma concentrations (pg/ml) per sampling time for comparative example B (intravenous single dose administration of buprenorphine 0.3mg) is provided in table 7 below:

the maximum concentration mean (Cmax) (pg/ml) summary measured in comparative examples A-C is provided in Table 8 below:

a summary of the mean Tmax values obtained for comparative examples A-C is given in Table 9 below:

table 10 below provides a summary of the areas under the (AUC) (0-t) curves for comparative examples A-C:

pharmacodynamics were determined by VAS "drug action" observations. The query subject "do you feel the effect of the drug? The subject then rated the project by placing vertical markers along a 100mm Visual Analog Scale (VAS) of "none at all" at one end and "very many" at the other end. The "drug effect" was estimated before each blood sample taken in the study. VAS was used before blood sampling to elicit the following side effects: nausea, dizziness; and drowsiness. Due to the number of samplings, an asymmetric blood sample was used in this study.

The pharmacokinetic results (concentration (pg/ml) versus time) in comparative examples A-C are shown in FIGS. 3-5, respectively. Fig. 4 shows the values obtained for the plasma concentration divided by 100. The pharmacodynamic results (PD Variables (VAS)) of comparative examples A-C are shown in FIGS. 6-8, respectively.

For figure 5, the curves demonstrate the effect of the dermal drug reservoir described herein, assuming a buprenorphine plasma concentration of 100pg/ml is the lowest effective concentration. Examination of the end of the curve beginning at the point in time when the transdermal delivery device was removed from the patient's skin showed that the buprenorphine plasma concentration remained equal to or greater than 100pg/ml for an additional approximately 24 hours (i.e., 216 hours to 240 hours). Thus, it can be said that there is analgesia for the additional 24 hours after removal of the device from the patient's skin. Of course, buprenorphine plasma concentrations are present during that period, and analgesia will be linked by those skilled in the art. In addition, because the drug has receptor binding properties and it has been reported that the clinical half-life of the drug may be several days, the analgesic effect may be able to last longer than 7 days (e.g., about 10 days), assuming the device is removed from the skin 7 days after initial use.

Comparative examples D to F

Comparative example 1 biological equivalence between a buprenorphine transdermal delivery device and patches made in the same manner and of different sizes and therefore containing varying amounts of buprenorphine.

Comparative example D a patch of the same size and containing buprenorphine as in example 1 was used. The transdermal patch contained a total of 10mg buprenorphine and had an active surface area of 12.5cm²The patch size is 30.6cm². In comparative example E, two patches were employed, each patch containing a total of about 5mg of buprenorphine and an active surface area of 6.25cm²The patch size is 19.4cm². Comparative example F the dose ratio (proportionality) of a buprenorphine transdermal delivery device (patch) with twice the dose of example 1 can be determined. In comparative example F, the total amount of buprenorphine contained in the transdermal patch was 20mg and the active surface area was 25cm²The patch size is 51.8cm². The study was performed by a 3-way cross-over design. The patch was left in place for 72 hours and then removed.

Table 11 provides a summary of the mean plasma buprenorphine concentrations (pg/ml) per sampling time for comparative example D:

table 12 provides a summary of the pharmacokinetic parameters for comparative example D:

table 13 provides a summary of the buprenorphine mean plasma concentrations of comparative example E:

table 14 provides a summary of the pharmacokinetic parameters for comparative example E:

table 15 provides a summary of the buprenorphine mean plasma concentrations of comparative example F:

table 16 provides a summary of the dose-corrected pharmacokinetic parameters for comparative example F. Values were calculated from the Cmax value (which is half the value actually reported).

Table 17 provides a summary of the buprenorphine patch residual amounts for each of comparative examples D-F:

the pharmacokinetic results (concentration (pg/ml) vs. hour) for comparative examples D-F are shown in FIGS. 9-11, respectively. FIGS. 12-14 show the pharmacodynamic results (PD Variables (VAS)) for comparative examples A-C, respectively.

Conclusion

To facilitate an understanding of the results obtained by comparing the methods of the present invention and the comparative examples, the following table is provided.

Table 18 provides a direct comparison of the plasma concentrations obtained for example 1(10mg buprenorphine patch maintained in contact with the skin of the subject for 7 days) with comparative example a (20mg buprenorphine patch retained on the skin of the subject for 3 days and then removed) and comparative example C (20mg buprenorphine patch applied to the skin of the subject for 3 days and removed after being left on the skin of the subject, and so on for 3 consecutive times). Comparative examples a and C are also expressed as 50% of the plasma concentration per period in order to compare plasma concentrations.

The data in table 18 show that, surprisingly, in example 1 (patch maintained on the skin for 7 days), there are plasma levels effective to provide analgesia even after 7 days of patch application; in comparative example a (patch removed after 3 days), on the other hand, blood levels dropped significantly once the patch was removed, so that plasma levels were present shortly after patch removal where buprenorphine doses were not effectively treated. On the other hand, look again at comparative example C. It is clear that plasma levels obtained from 3 consecutive days of buprenorphine patch administration resulted in a significant increase in Cmax levels over the daily dosing period. This fact can be confirmed by the time-dependent plasma concentration graph provided in comparative example C in fig. 3. In contrast, in example 1, plasma levels were substantially maintained over the 72-168 hour period following patch application. The results show that the method of the invention is surprisingly effective in reducing the total plasma concentration of buprenorphine required for a patient to experience effective analgesia. Furthermore, comparing the VAS results illustrated in example 1 with comparative example C, it is clear that the method of example 1 has significantly reduced side effects over the 7 day dosing period. In terms of a non-transdermal mode of administration, the present invention also achieves the additional benefit of avoiding the high peak plasma concentrations that have been achieved in the prior art by intravenous administration. For example, in comparative example B, a Cmax greater than about 30,000pg/ml was obtained.

Table 19 provides a direct comparison of plasma concentrations for example 1(10mg buprenorphine patch maintained in contact with the subject's skin for 7 days) and comparative example D (same 10mg buprenorphine patch was retained on the subject's skin for only 3 days, then removed) and comparative example E (two 5mg buprenorphine patches were maintained on the subject's skin for only 3 days, then removed):

the results shown in table 19 confirm that: the method of the invention provides effective plasma concentrations within 7 days; whereas the patch (or patches) containing the same dose was removed after 3 days, the buprenorphine plasma levels suddenly dropped over the following 24 hours to a level indicating that the buprenorphine dose was not therapeutically effective. This result is surprising in view of the fact that the patches can only provide effective analgesic levels of buprenorphine over a 3 day period-these patches cannot provide effective plasma levels of buprenorphine over a much longer period. (it must be noted that the absolute values of the mean plasma concentrations of example 1 and comparative example cannot be directly compared, since these results are from different studies involving different subjects, etc.).

Other surprising results can be seen from the data provided in table 20 below, which compares the residual buprenorphine content of the transdermal delivery devices of example 1 and certain comparative examples, as well as their relative release rates:

RR-relative Release Rate

The total amount of buprenorphine released (1.4mg) for example 1 can be expressed as an average of 0.2mg buprenorphine administered per day over a 7 day dosing period. In contrast, comparative example E (same patch over 3 days) released 1.23mg in total, which could be expressed as 0.41mg buprenorphine administered per day. Comparing the cumulative amount released in example 1 and comparative example D, it can be seen that the dose obtained in the present invention (mg/patch/day) is half the dose administered according to the prior art method. Furthermore, it is evident that almost all buprenorphine doses in example 1 were released within the first 72 hours (3 days) -1.23mg was released from a 10mg patch within 3 days, which is 87.86% of the 1.4mg released from the same patch within 7 days. Surprisingly, analgesia is maintained over a 72-168 hour dosing period even with very low amounts of buprenorphine released from a 10mg patch.

Moreover, the results show that buprenorphine is released substantially according to first order kinetics within the first 72 hours, whereas buprenorphine is released substantially according to zero order kinetics within 72-168 hours after administration. This can be confirmed from the plasma concentration profile provided in example 1 of figure 1. Thus, within the first 72 hours after administration according to the invention, a relative release rate of 17.1 μ g/hour (1.23mg divided by 72 hours) was obtained; whereas within 72-168 hours after administration according to the invention the relative release rate may decrease to only 1.77 mug/hour (1.40-1.23 mg-0.17 mg, 0.17mg divided by 96 hours), but the same level of buprenorphine analgesia in human patients may be maintained as effective.

Example 2

In example 2, the method of the invention was carried out by different modes of administration (i.e. intravenous infusion). The time-varying manner in which plasma concentrations seen in the present invention may be achieved by intravenous infusion using injectable parenteral forms of buprenorphine (e.g., buprenorphine hydrochloride suitably diluted in an intravenous infusion solution). The infusion rate can be controlled with a programmed infusion pump to provide the desired plasma concentration profile. The infusion rate over a given period of time may be determined and adjusted based on pharmacodynamic parameters such as pupil size (pupillometer) or pain relief (analgesia), or the plasma concentration of buprenorphine at any particular point in the period may be determined based on the results of a suitable biological assay. In addition, pharmacokinetic model design methods can be used to design models of the desired curves; this allows the desired profile to be estimated without pharmacokinetic or pharmacodynamic monitoring. However, periodically determining the plasma concentration makes the model more accurate and allows further adjustment of the infusion rate.

According to the method set out above, the following mean plasma concentrations were obtained: (ii) a mean plasma concentration of about 1 to 28pg/ml at about 6 hours from the start of the dosing period; at about 12 hours after the start of the dosing period, the mean plasma concentration is about 14-74 pg/ml; at about 24 hours after the start of the dosing period, the mean plasma concentration is about 30-161 pg/ml; at about 36 hours after the start of the dosing period, the mean plasma concentration is about 51-188 pg/ml; at about 48 hours after the start of the dosing period, the mean plasma concentration is about 62-246 pg/ml; at about 60 hours after the start of the dosing period, the mean plasma concentration is about 79 to 246 pg/ml; at about 72 hours after the start of the dosing period, the mean plasma concentration is about 85-263 pg/ml; at about 96 hours after the start of the dosing period, the mean plasma concentration is about 92-263 pg/ml; at about 120 hours after the start of the dosing period, the mean plasma concentration is about 94-263 pg/ml; at about 144 hours after the start of the administration period, the mean plasma concentration is about 86-243 pg/ml; (for a 7 day dosing period) the mean plasma concentration was about 77-210pg/ml at about 168 hours after the start of the dosing period.

It will be apparent to those skilled in the art that various modifications can be made in the present invention without departing from the scope of the invention. For example, many different transdermal delivery devices may be employed in order to achieve the relative release rates and plasma concentrations described herein. In addition, the mean plasma concentration for a particular patient population at a particular described time point during the dosing period may also differ from the plasma concentration at that time point described herein. Such obvious variations are considered to be included within the scope of the appended claims.

Claims (3)

1. Use of buprenorphine in the manufacture of a transdermal patch for the treatment of pain during 168 hours of administration by contact with the skin of a patient for 5 to 8 days, wherein

The transdermal patch comprises an adhesive composition containing 10% by weight of a buprenorphine base, 10-15% by weight of levulinic acid, 10% by weight of a softening agent, 55-70% by weight of a polyacrylate, and 0-10% by weight of polyvinylpyrrolidone; wherein the total dosage of buprenorphine is 10mg, and the active surface area is 12.5cm²The patch size is 30.6cm²。

2. The use of claim 1, wherein the transdermal patch provides a mean relative release rate of 3-86 μ g/hr and an approximately first order increase in buprenorphine plasma levels from the start of the dosing period of at least 5 days to 72 hours after the start of the dosing period; the transdermal patch provides a mean relative release rate of 0.3-9 μ g/hr and a substantially zero order fluctuation in buprenorphine plasma levels from 72 hours to the end of the dosing period of at least 168 hours after the start of the dosing period.

3. The use according to claim 1, wherein the transdermal patch provides a mean relative release rate over a 168 hour dosing period of:

the average relative release rate is 3-86 mug/h from the beginning of the administration period to 72 hours after the beginning of the administration period; and

the average relative release rate is 0.3-9 μ g/hr from 72 hours after the start of the administration period to the end of the administration period.